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Successful in vivo blockade of CD25 (high-affinity interleukin 2 receptor) on T cells by administration of humanized anti-Tac antibody to patients with psoriasis,☆☆,

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Abstract

Background: Daclizumab is a humanized antibody to the α-subunit (CD25) of the interleukin 2 (IL-2) receptor that blocks normal IL-2 binding to this receptor. Because IL-2 is a major stimulus for T-cell growth, blockade of the IL-2 receptor could be useful in treating T-cell-mediated (autoimmune) diseases. Objective: Our purpose was to determine whether adequate concentrations of antibody were achieved in circulating blood and in psoriatic skin lesions to saturate CD25 receptors. We also intended to measure clinical effect and safety of this agent when used alone (without other immunosuppressive drugs) in psoriasis. Methods: Nineteen patients with psoriasis in two centers received daclizumab at an initial dose of 2 mg/kg, then 1 mg/kg at weeks 2, 4, 8, and 12. To determine whether CD25 was blocked in vivo, flow cytometric studies measured (1) expression of CD25 on CD3+ T cells derived from blood and (2) immuno-histochemistry measures of CD25+ cells done on pretreatment and posttreatment biopsy specimens. Patients were followed up clinically with photographs and Psoriasis Area and Severity Index scores. Results: This study showed a consistent blockade of CD25 in peripheral blood and tissue during the first 4 weeks of therapy while the dosing was every 2 weeks. Variable desaturation of receptors began after 4 weeks, which correlated with a reversal in disease improvement. Patients with a pretreatment Psoriasis Area and Severity Index score of less than 36 showed a mean reduction in severity by 30% at 8 weeks (P = .02). During the 16 weeks of treatment, a 44.8% decrease in expression of the IL-2 receptor α-subunit was found. The absolute T-cell counts were calculated and showed no significant changes during the course of the study. No significant adverse events were produced by daclizumab during this study. Conclusion: We therefore conclude that daclizumab is a well-tolerated agent that blocks CD25 expression in peripheral blood and skin. Furthermore, it may be useful in treating psoriasis in some patients. (J Am Acad Dermatol 2000;43:448–58.).

Section snippets

Patients

Nineteen adult patients (12 male, 7 female) with moderate to severe plaque-type psoriasis were sequentially enrolled into our study, which was approved by the Rockefeller University Hospital and University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School Institutional Review Boards. Enrollment excluded patients with guttate, erythrodermic, and pustular psoriasis. Of the 19, 17 had previously been treated with two or more systemic therapies, including phototherapy (UVB

Results

Eighteen of 19 patients completed the entire study. There were no significant adverse events in any patient. All routine laboratory values remained within normal limits during and for 2 months after infusions. As a safety measure, we calculated the total number of T cells during the course of therapy. The average absolute T-cell count before treatment was 1200. This remained unchanged until week 12 when there was a slight increase to 1674 (normal range, ~420-5000).

Our first objective was to

Discussion

Psoriasis is now recognized as disease that is induced and sustained by skin-infiltrating T-lymphocytes.11 Lesion-infiltrating lymphocytes include intraepidermal CD8+ T cells with the phenotype of cytotoxic effectors7 and CD4+ T helper type 1 cells that are capable of producing high levels of interferon gamma, tumor necrosis factor α, and other “effector” cytokines.6 Both of these T-cell subtypes express high levels of CD25 in psoriatic skin lesions compared with T cells that circulate.7 Given

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    Supported in part by a General Clinical Research Center Grant (M01-RR00102) from the National Center for Research Resources at the National Institutes of Health (NIH); by NIH grant AI39214; and by a grant from Hoffmann-LaRoche, Inc.

    ☆☆

    Reprint requests: James G. Krueger, MD, PhD, Laboratory Head, Laboratory for Investigative Dermatology, The Rockefeller University, 1230 York Ave, Box 178, New York, NY 10021-6399. E-mail: [email protected].

    J Am Acad Dermatol 2000;43:448–58.

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